Cosmetic compositions containing substituted azole and methods for improving the appearance of aging skin

ABSTRACT

Methods of improving the appearance of aging skin that include applying a cosmetic composition to a target skin surface having one or more signs of aging. The cosmetic composition includes a substituted azole. In some instances, the substituted azole compound is 1-phenylimidazole, 4-phenylimidazole, or combinations thereof. An effective amount of the cosmetic composition is applied for a period of time sufficient to improve the appearance of at least one sign of aging skin.

FIELD OF THE INVENTION

Cosmetic compositions and methods for improving the appearance of agingskin using substituted azole compounds, particularly 1-phenylimidazole,4-phenylimidazole, or combinations thereof.

BACKGROUND OF THE INVENTION

The epidermis, the outermost layer of the skin, comprises a cellularcontinuum of four layers: the stratum corneum, the granular layer, thespinous layer, and the basal layer. Each cellular layer in the epidermisrepresents various stages along a process in which basal epidermalkeratinocytes undergo a continuous cycle of proliferation,differentiation, and apoptosis, moving upward from the basal layer tofinally yield corneocytes. These corneocytes form the cornified layerknown as the stratum corneum.

Basal keratinocytes reside at the lower portion of the epidermis. Thesemitotically active cells undergo a proliferative cycle to generatedaughter cells that are physically dislocated upward into the spinousand granular layers and undergo the process of differentiation intocorneocytes. On passing through the spinous and granular layers, thecells undergo morphological changes that render them flatter instructure as they lose their cellular viability, undergo alternatekeratin expression profiles, and transform into cellular remnants. Onaverage, a younger-aged epidermis turns over in about one month,shedding the older cells and replacing them with newer ones, but thisprocess can increase to over forty days in older skin.

The stratum corneum's corneocytes remain connected to one other viaproteins and lipids, creating a protective barrier between the organismand its outside environment. This tightly regulated epidermalpermeability barrier functions as a physical and selective barrieragainst chemical and biological insults. Important functions of thisbarrier include attenuation of the penetration of free radicals andprevention of penetration of harmful radiation, including UV radiation,into deeper layers. The stratum corneum also acts as a permeabilitybarrier and functions to prevent loss of body moisture to the outsideenvironment. Dysfunction of this barrier can lead to chronic skinconditions, diseases, and in extreme cases can even threaten theviability of the organism.

Skin aging is a multifactorial process driven by both intrinsic(chronological aging) and extrinsic (environmental) factors, includingultraviolet (UV) exposure, environmental toxins, pollutants, andsmoking. It is well known in the art that the ability of the stratumcorneum to cyclically generate new layers of skin diminishes with age sothat the stratum corneum turnover rate is substantially reduced in agedskin, with the cornified layer becoming gradually thinner. This resultsin a reduction in the functioning capacity of the barrier so thatharmful stimuli penetrate the stratum corneum more easily, leading toUV-damage, for example, of the underlying dermal layers, degradation ofcollagen and elastin, and eventually manifests in appearance aswrinkling and skin atrophy. Thinning of the stratum corneum by the sumof intrinsic and extrinsic aging factors increases the visibleappearance of fine lines and wrinkles. Further, the barrier suffers froman age-related increase in permeability to free radicals and a reductionin the amount of lipid in the intercellular matrix, decreasing barriercapacity to diffuse toxins from deeper layers. Recovery capacity of thebarrier to environmental insult is also substantially reduced with age.

Thus, the skin's epidermal barrier function is key to the skin's abilityto regenerate and protect itself from the appearance of aging signs suchas fine lines and wrinkles. Accordingly, it would be desirable toprovide compositions and methods of treatment that can improve theskin's epidermal functioning and thus also improve the appearance ofaging skin.

SUMMARY OF THE INVENTION

The present invention provides a method of improving the appearance ofaging skin comprising: (a) identifying an aging skin surface; and (b)applying to the skin surface a composition comprising an effectiveamount of a substituted azole compound represented by the structure:

where:

-   R1: is an alkyl or phenyl electron donating group-   R2: is hydrogen-   R3 and R4 (which may be identical or different): do not form a fused    ring, and each is independently selected from the monodentate group    consisting of H, alkyl, and phenyl.

The substituted azole compound can be one or a combination of more thanone substituted azole compound. In some embodiments, the substitutedazole compound is 1-phenylimidazole:

In other embodiments, the substituted azole compound is4-phenylimidazole:

In some compositions, the substituted azole compound is a combination of1-phenylimidazole and 4-phenylimidazole.

The composition comprises an effective amount of the substituted azolecompound. In some embodiments, the composition comprises up to 20%, 10%,5%, 3%, or 1%, and alternatively at least 0.001%, 0.01%, 0.1%. 0.2%, or0.5%, by weight of the total composition, of the substituted azolecompound. Suitable ranges can include any combination of the lower andupper limits, for example from 0.001% to 20%; from 0.001% to 1%; or from0.5% to 10%, by weight of the composition, of the substituted azolecompound. The amounts listed herein are only to be used as a guide, asthe optimum amount will depend on the specific substituted azolecompound selected, since their potency does vary considerably.

The composition also comprises a dermatologically acceptable carrier.The composition can also include optional ingredients as desired, suchas a sunscreen active, an anti-inflammatory agent, and/or a skin toneagent. Exemplary skin tone agents can include vitamin B3 compounds,sugar amines, hexamidine compounds, salicylic acid, and/or1,3-dihydroxy-4-alkylbenzene.

Alternatively, optional ingredients can be delivered in a secondcomposition that is applied contemporaneously as part of a regimen. Insuch embodiments, a first composition comprises the substituted azolecompound and a second composition comprises desired optionalingredients.

The composition is applied for a period of time sufficient to improvethe appearance of one or more signs of aging skin. In particularembodiments, the composition is applied to a facial skin surface, whichmay include the forehead, perioral, chin, periorbital, nose, and/orcheek.

The present invention may take other forms. Further forms of the presentinvention will be appreciated in the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of improving the appearance ofaging skin. As used herein, “improving the appearance of aging skin” isbroad enough to include not only minimizing and/or preventing and/ordelaying at least one sign of aging skin, but also treating aging skinto effect visually and/or tactilely perceptible positive change (i.e.,benefit) in appearance and/or feel of at least one sign of aging skin.

“Signs of aging skin” include, but are not limited to, all outwardlyvisible and/or tactilely perceptible manifestations due to skin aging.These signs may result from processes which include, but are not limitedto, the development of textural discontinuities such as wrinkles andcoarse deep lines, fine lines, crevices, bumps, large pores, unevennessor roughness; loss of skin elasticity (e.g., due to loss, damage and/orinactivation of functional skin elastin, resulting in such conditions aselastosis, sagging, and/or loss of skin recoil from deformation);thinning of keratinous tissue (e.g., the epidermis and/or dermis and/orsub-dermal layers of the skin); hyperpigmentation (e.g., age spots);decreasing the convolution of the dermal-epidermal border (also known asthe rete ridges); skin discoloration (e.g., blotchiness, sallowness);abnormal differentiation; hyperkeratinization; collagen breakdown, andother histological changes in the stratum corneum, dermis, andepidermis.

The method of the present invention comprises: (a) identifying an agingskin surface; and (b) applying to the skin surface a compositioncomprising an effective amount of a substituted azole compound for aperiod of time sufficient to improve the appearance of one or more signsof aging skin. Unless otherwise indicated expressly or by context, theterm “substituted azole” refers to one or more substituted azolecompounds represented by the structure set forth herein. “Aging skinsurface” means a skin surface having one or more signs of aging skin.“Applying” means to apply or spread the composition onto a human skinsurface (i.e., epidermis).

An “effective amount” of a substituted azole compound or of acomposition containing such substituted azole compound means an amountof such compound or composition sufficient to significantly (i.e.,statistically significant) improve the appearance of one or more signsof aging skin. The particular amount that is effective depends on thespecific substituted azole compound selected, since the potency of thesecompounds does vary.

In some embodiments, the composition comprises up to 20%, 10%, 5%, 3%,or 1%, and alternatively at least 0.001%, 0.01%, 0.1%. 0.2%, or 0.5%, byweight of the total composition, of the substituted azole compound.Suitable ranges can include any combination of the lower and upperlimits, for example from 0.001% to 20%; from 0.001% to 1%; or from 0.5%to 10%, by weight of the composition, of the substituted azole compound.These exemplary amounts are only to be used as a guide, as the optimumamount will depend on the potency of the specific substituted azolecompound. Hence, the amount of some compounds useful in the presentinvention may be outside the ranges set forth herein. Determining theeffective amount for the chosen substituted azole compound is within theknowledge of one skilled in the art.

The composition further comprises a dermatologically acceptable carrier.The term “dermatologically acceptable” as used herein means that thecompositions or components described are suitable for use in contactwith human skin tissue without undue toxicity, incompatibility,instability, allergic response, and the like.

The substituted azole compound of the present invention is representedby the structure:

where: R1 is an alkyl or phenyl electron donating group; R2 is hydrogen;R3 and R4 (which may be identical or different) do not form a fused ringand each is independently selected from the monodentate group consistingof H, alkyl, and phenyl. The N-substituted azole compound can be one ora combination of more than one substituted azole compound.

In some embodiments, the substituted azole compound is1-phenylimidazole:

In other embodiments, the substituted azole compound is4-phenylimidazole:

In some compositions, the substituted azole compound is a combination of1-phenylimidazole and 4-phenylimidazole.I. Compositions

The present invention relates to various compositions and, morespecifically, to compositions for application to a skin surface. Thecompositions may be in a wide variety of product forms that include, butare not limited to, solutions, suspensions, lotions, creams, gels,toners, sticks, pencil, sprays, aerosols, ointments, cleansing liquidwashes and solid bars, shampoos and hair conditioners, pastes, foams,powders, mousses, shaving creams, wipes, strips, patches,electrically-powered patches, wound dressing and adhesive bandages,hydrogels, film-forming products, facial and skin masks (with andwithout insoluble sheet), make-up such as foundations, eye liners, andeye shadows, and the like. The composition form may follow from theparticular dermatologically acceptable carrier chosen, if present in thecomposition.

A. Substituted Azole Compound

Compositions of the present invention comprise an effective amount of asubstituted azole compound represented by the structure:

where: R1 is an alkyl or phenyl electron donating group; R2 is hydrogen;R3, and R4 (which may be identical or different) do not form a fusedring and each is independently selected from the monodentate groupconsisting of H, alkyl, and phenyl.

Electron donating groups have a lone pair of electrons on the atomdirectly bonded to the ring. The electron donating group increases thearomatic ring's electron density through a resonance donation effect.This is a very stable resonance form, as the resulting carbocation isstabilized by the electron donating group. More stable intermediates(the carbocation) have lower transition state energies and thus a fasterreaction rate, resulting in substituents being preferentially directedto positions where they are in conjugation with the aromatic ring.Electron donating groups on an aromatic ring are said to be“activating”, because they increase the rate of the second substitutionso that it is higher than that of the standard aromatic molecule.

Applicant has surprisingly discovered that this class of substitutedazole compounds can alleviate the signs of aging when applied topically.Not to be limited by theory, it is believed that the effectiveness ofthese particular substituted azole compounds is due to their ability toinhibit cytochrome P450 (“CYP”) enzyme activity, and thus function asretinoic acid metabolism blocking agents (“RAMBA”s).

1. Mechanism of Action

Researchers have long appreciated that vitamin A is a critical regulatorof growth and differentiation of developing and adult mammalian skin.Vitamin A deficiency causes disruption of normal cellular homeostaticmechanisms, resulting in impairment of skin barrier function.All-trans-retinoic acid (“ATRA”), the biologically most activemetabolite of vitamin A, plays a major role in cellular differentiationand proliferation of epithelial tissue.

The main source of retinoic acid (“RA”) in humans, excluding therapeuticdosing, is through synthesis from dietary precursors such asbeta-carotene and retinyl palmitate. Vitamin A is stored primarily inliver stellate cells as retinyl esters, which are hydrolyzed inhepatocytes by retinyl ester hydrolases to retinol. Retinol, theprecursor of RA, is the main circulating retinoid and is obtained fromretinol through a two-step synthesis in which the conversion of retinolto retinal is the rate limiting step. Retinol is oxidizedintracellularly by retinol dehydrogenases to retinal, and retinal isthen metabolized by NAD/NADP-dependent retinal dehydrogenases to RA.

While RA is synthesized endogenously in the body from dietaryprecursors, it may also be administered exogenously, such as via topicalretinoid application. Research has shown that ATRA has the ability tonot only prevent but also to repair skin cell damage. With aging, theskin's endogenous ATRA levels are depleted, leading to impairedfunctioning of the epidermal barrier. Thus, maintaining elevated levelsof ATRA is critical in order to maintain barrier function integrity andthus prevent and/or improve the appearance of aging skin.

Unfortunately, therapeutic administration of exogenous (e.g., topical)retinoids has challenges. Although they can be very effective, retinoidsare not well tolerated by many people. Common side effects associatedwith topically applied retinoids include burning and stinging of theskin, peeling, redness, and heightened photosensitivity. Furthermore,the therapeutic effect decreases over time, necessitating the use ofincreasingly higher retinoid levels to maintain the same level ofbenefit. Retinoid side effects are largely dose-dependent. As a result,many individuals with sensitivity to retinoids cannot tolerate levelssufficient to provide the desired positive results. Additionally,retinoids are rapidly metabolized by the body, resulting in the need forhigher doses than would otherwise be required to achieve the desiredtherapeutic effects.

An approach to overcoming the drawbacks associated with exogenousretinoid therapy and/or the rapid elimination of ATRA is to amplifyendogenous levels of ATRA by inhibiting the CYP-mediated catabolism ofRA using agents known as retinoic acid metabolism blocking agents(RAMBAs). RAMBAs prevent the in vivo catabolism of ATRA by inhibitingthe CYP-mediated catabolism enzymes responsible for ATRA eliminationInhibiting the CYP enzymes blocks their metabolism and prolongs RAresidence time at the site of action, thus increasing the level ofendogenous ATRA within the cells. This results in higher in vivo ATRAconcentrations, thus reducing and/or preferably eliminating the need toapply topical exogenous retinoids to achieve the desired effect.

2. In vitro Cytochrome P450 Inhibition Assay

Cytochrome P450 is a large and diverse group of enzymes that catalyzethe oxidation of organic substances. Some members of the CYP familycontribute to the elimination of ATRA by catalyzing its 4-hydroxylationin the mammalian liver and skin, including that of humans as well asswine. Applicant evaluated the potential RAMBA activity of severalazoles using pig liver microsomes, a rich source of CYP activity,comprising many different CYP 450 isoforms. Therefore, this approach,while a reasonable way to assess CYP inhibitors with broad activitiesmay or may not be the best way to discover RAMBAs with selectivity forthe skin, which has a much more narrow complement of CYP expression. Asunderstanding in this area has progressed, a more specific CYPinhibition assay can be used to provide better predictivity of activityin human skin. Nevertheless, this assay may still be used as a generalpredictor of overall CYP activity.

As shown in Example 2, several compounds were screened through an invitro CYP assay using pig liver microsomes to determine theireffectiveness as CYP inhibitors and correspondingly potential RAMBAs. Itis clear from the data in Table 2 that with the exception of thepositive control, ketoconazole, none of the tested materials yieldedIC₅₀ values at concentrations less than 10 μM. This is likely due to thediversity of CYPs in the microsomal sample, which could dilute theinhibitory activity of CYPs most relevant for ATRA metabolism in theskin.

The metabolism of retinoic acid and vitamin D in the skin isincompletely understood, but there is evidence for the involvement ofCYP26A1, CYP3A4 and CYP2C8 in catalyzing the 4-hydroxylation ofall-trans RA to 4-hydroxy-RA. It is believed, without being limited bytheory, that CYP3A4 may be particularly important for ATRA metabolism inthe skin. This is because CYP3A4 is expressed in skin, involved in RAmetabolism, a CYP with one of the broadest substrate specificities ofall of the known CYPs and available as a human recombinant protein in acommercial kit. Thus, a commercially available CYP3A4 assay was used asa surrogate to predict RAMBA potential in the skin. The method isdescribed in more detail below in Example 3, and the results areillustrated in Table 3. As illustrated in Table 3, the IC₅₀ values ofseveral compounds indicate strong inhibition of CYP3A4 when the IC₅₀value is ≦10 μM and weak or no inhibition when the IC₅₀ value is >10 μM.

Several simple imidazole structures showed a remarkably high level ofinhibitory activity relative to the positive control, ketoconazole. Ofparticular note are the results for 1-, 2-, and 4-phenylimidazole. Thesematerials are positional isomers, differing from one another only in thelocation of the phenyl group relative to the imidazole ring. The 1- and4-phenylimidazole had IC₅₀ values in the same range as climbazole, aknown 4-hydroxylase inhibitor that is marketed as an antifungal active.However, the 2-phenylmidazole analogue lacked any significant inhibitoryactivity, indicating that positioning of the imidazole ring relative tothe phenyl group seems to play an important structural component for CYPenzyme interaction. Thus, 1- and 4-phenylimidazole elicit CYP inhibitoryactivity, while 2-phenylimidazole does not. Accordingly, 1- and 4—canserve as effective RAMBAs, boosting the endogenous ATRA concentration.These results demonstrate that substituted azole compounds having theparticular structure set forth herein function differently from othercompounds, even when those compounds are positional isomers. (Thechemical structures of the materials tested in Example 2 can be found inTable 3 of Example 3. For brevity, the structures are not duplicated byinclusion in both tables.)

3. In vitro CYP/CYP3A4 Inhibition Assay

The commercially available P450-GLO™ Assay kit (Promega Corporation,Madison Wis.) was used to screen various compounds for potential CYPactivity, specifically CYP3A4A inhibition activity. CYP3A4A is thoughtto be among the primary CYP isoforms responsible for retinoic acidmetabolism in the skin.

Three benchmark agents, liarozole, climbazole, and ketoconazole, wereassessed for CYP3A4 inhibition to confirm that the inhibition activity(the IC₅₀ for CYP inhibition) measured by the assay corresponded to theactivity reported by the published literature.

The results set forth in Table 3 show that the substituted azolecompounds having the specific structure set forth herein are CYPinhibitors, and thus function as RAMBAs. Of particular note, once again,are the results for the positional isomers 1-, 2-, and4-phenylimidazole. Consistent with the results from Example 2's CYP invitro assay, the R1 substituted 1-phenylimidazole and the R3 substituted4-phenylimidazole showed inhibitory activity in the CYP3A4 assay, butthe R2 substituted 2-phenylimidazole analogue did not. This underscoresthe importance of the substituted azole structure to the CYP enzymeinteraction.

As used in Table 3, “hit” or “no hit” mean, respectively, stronginhibition (IC₅₀ value <10 μM) or weak/no inhibition (IC₅₀ value >10 μM)of CYP3A4.

B. Dermatologically Acceptable Carrier

The compositions of the present invention may also comprise adermatologically acceptable carrier (which may be referred to as“carrier”) for the composition. The phrase “dermatologically acceptablecarrier”, as used herein, means that the carrier is suitable for topicalapplication to the skin surface, has good aesthetic properties, iscompatible with the actives in the composition, and will not cause anyunreasonable safety or toxicity concerns. In one embodiment, the carrieris present at a level of from 50% to 99%, or from 60% to 98%, or from70% to 98%, or, alternatively, from 80% to 95%, by weight of thecomposition.

The carrier can be in a wide variety of forms. Non-limiting examplesinclude simple solutions (e.g., aqueous, organic solvent, or oil based),emulsions, and solid forms (e.g., gels, sticks, flowable solids, oramorphous materials). In certain embodiments, the dermatologicallyacceptable carrier is in the form of an emulsion. Emulsion may begenerally classified as having a continuous aqueous phase (e.g.,oil-in-water and water-in-oil-in-water) or a continuous oil phase (e.g.,water-in-oil and oil-in-water-in-oil). The oil phase of the presentinvention may comprise silicone oils, non-silicone oils such ashydrocarbon oils, esters, ethers, and the like, and mixtures thereof.

The aqueous phase typically comprises water. However, in otherembodiments, the aqueous phase may comprise components other than water,including but not limited to water-soluble moisturizing agents,conditioning agents, anti-microbials, humectants and/or otherwater-soluble skin care actives. In one embodiment, the non-watercomponent of the composition comprises a humectant such as glycerinand/or other polyols. However, it should be recognized that thecomposition may be substantially (i.e., less than 1% water) or fullyanhydrous.

A suitable carrier is selected to yield a desired product form.Furthermore, the solubility or dispersibility of the components (e.g.,extracts, sunscreen active, additional components) may dictate the formand character of the carrier. In one embodiment, an oil-in-water orwater-in-oil emulsion is preferred.

Emulsions may further comprise an emulsifier. The composition maycomprise any suitable percentage of emulsifier to sufficiently emulsifythe carrier. Suitable weight ranges include from 0.1% to 10%, or 0.2% to5% of an emulsifier, based on the weight of the composition. Emulsifiersmay be nonionic, anionic or cationic. Suitable emulsifiers are disclosedin, for example, U.S. Pat. Nos. 3,755,560, 4,421,769, and McCutcheon'sDetergents and Emulsifiers, North American Edition, pages 317-324(1986). Suitable emulsions may have a wide range of viscosities,depending on the desired product form.

The carrier may further comprise a thickening agent as are well known inthe art to provide compositions having a suitable viscosity andrheological character.

C. Skin Tone Agent

In some embodiments, it may be desirable to include a skin tone agent inthe composition. The skin tone agents can be included to further improveoverall skin tone. When present, the compositions of the presentinvention can contain up to 50%, 40%, 30%, 20%, 10%, 5%, or 3%, byweight of the composition, of the skin tone agent. When present, thecompositions of the present invention can contain at least 0.001%,0.01%, 0.1%, 0.2%, 0.5%, or 1%, by weight of the composition, of theskin tone agent. Suitable ranges include any combination of the lowerand upper limits including suitable ranges from 0.1% to 50%; from 0.2%to 20%; or from 1% to 10%, by weight of the composition, of the skintone agent. The amounts listed herein are only to be used as a guide, asthe optimum amount of the skin tone agent will depend on the specificactive selected since their potency does vary considerably.

Suitable skin tone agents include, but are not limited to, sugar amines,vitamin B3 compounds, arbutin, deoxyarbutin,1,3-dihydroxy-4-alkylbenzene such as hexylresorcinol, sucrosedilaurante, bakuchoil (4-[(1E,3S)-3-ethenyl-3,7-dimethyl-1,6octadienyl]phenol or monterpene phenol), pyrenoine (available fromBiotech Marine, France), panicum miliaceum seed extract, arlatone dioicacid, cinnamic acid, ferulic acid, achromaxyl, methyl nicotinamide, oilsoluble licorice extract, folic acid, undecylenic acid (i.e., undecenoicacid), zinc undecylenate, thiamine (Vitamin B1) and its hydrochloride,L-tryptophan, helianthus annuus (sunflower) and vitis vinifera (grape)leaf extract, carnosine (i.e., dragosine), methyl gentisate,1,2-hexandiol and 1,2-octandiol (i.e., combination sold as Symdiol 68 bySymrise AG, Germany), inositol, decylenoylphenylalanine (e.g., soldunder the tradename Sepiwhite by Seppic, France), kojic acid, hexamidinecompounds, and salicylic acid.

In certain embodiments, the skin tone agent is selected from vitamin B3compounds, sugar amines, hexamidine compounds, salicylic acid, and a1,3-dihydroxy-4-alkylbenzene such as hexylresorcinol. As used herein,“vitamin B₃ compound” means a compound having the formula:

wherein R is —CONH₂ (i.e., niacinamide), —COOH (i.e., nicotinic acid) or—CH₂OH (i.e., nicotinyl alcohol); derivatives thereof; and salts of anyof the foregoing. As used herein, “sugar amine” includes isomers andtautomers of such and its salts (e.g., HCl salt) and its derivatives.Examples of sugar amines include glucosamine, N-acetyl glucosamine,mannosamine, N-acetyl mannosamine, galactosamine, N-acetylgalactosamine, their isomers (e.g., stereoisomers), and their salts(e.g., HCl salt). As used herein, “hexaminide compound” means a compoundhaving the formula:

wherein R¹ and R² are optional or are organic acids (e.g., sulfonicacids, etc.). In one embodiment, the hexamidine compound is hexamidinediisethionate.

Furthermore, the skin tone agent of the present invention can include axanthine compound. As used herein, “xanthine compound” means one or morexanthines, derivatives thereof, and mixtures thereof. Xanthine compoundsthat can be useful herein include, but are not limited to, caffeine,xanthine, 1-methyl xanthine, theophylline, theobromine, derivativesthereof, and mixtures thereof. In one embodiment, the compositioncomprises from about 0.1% to about 10% of a xanthine compound, inanother embodiment from about 0.5% to about 5% of a xanthine compound,and in yet another embodiment from about 1% to about 2% of a xanthinecompound.

D. Anti-Inflammatory Agents

Hyperpigmentation may result from skin inflammation. Transientinflammatory events triggering hyperpigmentation and, more specifically,post-inflammatory hyperpigmentation include, but are not limited to,acne lesions, ingrown hairs, scratches, insect bites, surfactant damage,allergens, and short-term UV exposure. Inflammation inducedhyperpigmentation including post-inflammatory hyperpigmentation may bemanaged by incorporating into the compositions of the present inventionan anti-inflammatory agent. When present, the compositions of thepresent invention can contain up to 20%, 10%, 5%, 3%, or 1% by weight ofthe composition, of the anti-inflammatory agent. When present, thecompositions of the present invention can contain at least 0.001%,0.01%, 0.1%, 0.2%, 0.3%, 0.5%, or 1%, by weight of the composition, ofthe anti-inflammatory agent. Suitable ranges include any combination ofthe lower and upper limits Exact amounts will vary depending upon thechosen anti-inflammatory agent; determining the appropriate amount iswithin the knowledge of one of skilled in the art.

Suitable anti-inflammatory agents include, but are not limited tononsteroidal anti-inflammatory agents (“NSAIDS” including but notlimited to ibuprofen, naproxen, flufenamic acid, etofenamate, aspirin,mefenamic acid, meclofenamic acid, piroxicam and felbinac), glycyrrhizicacid (also known as glycyrrhizin, glycyrrhixinic acid, andglycyrrhetinic acid glycoside) and salts such as dipotassiumglycyrrhizate, glycyrrhetenic acid, licorice extracts, bisabolol (e.g.,alpha bisabolol), manjistha (extracted from plants in the genus Rubia,particularly Rubia cordifolia), and guggal (extracted from plants in thegenus Commiphora, particularly Commiphora mukul), kola extract,chamomile, and sea whip extract (extracts from plant in the orderGorgonacea), derivatives of any of the foregoing, and mixtures thereof.

E. Sunscreen Actives

The compositions of the subject invention may comprise one or moresunscreen actives (or sunscreen agents) and/or ultraviolet lightabsorbers. As used herein, “sunscreen active” collectively includessunscreen actives, sunscreen agents, and/or ultraviolet light absorbers.Sunscreen actives include both sunscreen agents and physical sunblocks.Sunscreen actives may be organic or inorganic. Examples of suitablesunscreen actives are disclosed in Personal Care Product Council'sInternational Cosmetic Ingredient Dictionary and Handbook, ThirteenthEdition, as “sunscreen agents.”

Suitable sunscreen actives include 2-ethylhexyl-p-methoxycinnamate(commercially available as PARSOL™ MCX), 4,4′-t-butylmethoxydibenzoyl-methane (commercially available as PARSOL™ 1789),2-hydroxy-4-methoxybenzophenone, octyldimethyl-p-aminobenzoic acid,digalloyltrioleate, 2,2-dihydroxy-4-methoxybenzophenone,ethyl-4-(bis(hydroxypropyl))aminobenzoate,2-ethylhexyl-2-cyano-3,3-diphenylacrylate, 2-ethylhexyl-salicylate,glyceryl-p-aminobenzoate, 3,3,5-tri-methylcyclohexylsalicylate, menthylanthranilate, p-dimethyl-aminobenzoic acid or aminobenzoate,2-ethylhexyl-p-dimethyl-amino-benzoate, 2-phenylbenzimidazole-5-sulfonicacid, 2-(p-dimethylaminophenyl)-5-sulfonicbenzoxazoic acid, octocrylene,zinc oxide, benzylidene camphor and derivatives thereof, titaniumdioxide, and mixtures thereof.

When present, the compositions of the present invention can contain upto 20%, 10%, 5%, 3%, or 1% by weight of the composition, of thesunscreen active. When present, the compositions of the presentinvention can contain at least 0.001%, 0.01%, 0.1%, 0.2%, 0.3%, 0.5%, or1%, by weight of the composition, of the sunscreen active. Suitableranges include any combination of the lower and upper limits Exactamounts will vary depending upon the chosen sunscreen active and thedesired Sun Protection Factor (SPF), which is within the knowledge ofone of skilled in the art.

F. Other Optional Components

The compositions of the present invention may optionally contain avariety of other ingredients provided that they do not unacceptablyalter the benefits of the invention. When present, compositions of thepresent invention may contain from 0.0001% to 50%; from 0.001% to 20%;or, alternately, from 0.01% to 10%, by weight of the composition, of theoptional components. The amounts listed herein are only to be used as aguide, as the optimum amount of the optional components used in acomposition will depend on the specific active selected since theirpotency does vary considerably. Hence, the amount of some optionalcomponents useful in the present invention may be outside the rangeslisted herein.

The optional components, when incorporated into the composition, shouldbe suitable for use in contact with human skin tissue without unduetoxicity, incompatibility, instability, allergic response, and the like.The compositions of the present invention may include optionalcomponents such as anti-acne actives, desquamation actives,anti-cellulite agents, chelating agents, flavonoids, tanning active,non-vitamin antioxidants and radical scavengers, hair growth regulators,anti-wrinkle actives, anti-atrophy actives, minerals, phytosterolsand/or plant hormones, N-acyl amino acid compounds, antimicrobial orantifungal actives, and other useful skin care actives, which aredescribed in further detail in U.S. application publication No.US2006/0275237A1 and US2004/0175347A1.

The Personal Care Product Council's International Cosmetic IngredientDictionary and Handbook, Thirteenth Edition, describes a wide variety ofnon-limiting cosmetic and pharmaceutical ingredients commonly used inthe skin care industry, which are suitable optional components for usein the compositions of the present invention. Examples of theseingredient classes include: abrasives, absorbents, aesthetic componentssuch as fragrances, pigments, colorings/colorants, essential oils,anti-caking agents, antifoaming agents, antimicrobials, binders,biological additives, buffering agents, bulking agents, chelatingagents, chemical additives, colorants, cosmetic astringents, cosmeticbiocides, denaturants, drug astringents, emollients, externalanalgesics, film formers or materials, opacifying agents, pH adjusters,preservatives, propellants, reducing agents, sequestrants, skin coolingagents, skin protectants, thickeners viscosity modifiers, vitamins, andcombinations thereof.

II. Methods of Treatment

Various methods of treatment, application, regulation, or improvementmay utilize the aforementioned compositions. Identification of a regionof skin subject to the signs of aging may occur on any skin surface ofthe body. Skin surfaces of the most concern tend to be those nottypically covered by clothing, such as facial skin surfaces, hand andarm skin surfaces, foot and leg skin surfaces, and neck and chest skinsurfaces (e.g., décolletage). In particular, identification of theregion of aging skin may be on a facial skin surface including theforehead, perioral, chin, periorbital, nose, and/or cheek skin surfaces.

One suitable method of improving the appearance of aging skin includesthe step of topically applying a composition comprising an effectiveamount of substituted azole to the skin surface, wherein the compositionis applied for a period of time sufficient to improve the appearance ofthe aging skin.

The method may comprise the step of applying the composition to thepreviously identified area of aging skin, and/or an area where one seeksto prevent the appearance of aging skin. Many regimens exist for theapplication of the composition. The composition may be applied at leastonce a day, twice a day, or on a more frequent daily basis, during atreatment period. When applied twice daily, the first and secondapplications are separated by at least 1 to 12 hours. Typically, thecomposition may be applied in the morning and/or in the evening beforebed.

The treatment period is ideally of sufficient time to provide animprovement in the appearance of aging skin. The treatment period may beat least 1 week, and in some embodiments the treatment period may last 4weeks or 8 weeks. In certain embodiments, the treatment period willextend over multiple months (i.e., 3-12 months) or multiple years. Inone embodiment the composition is applied at least once a day during atreatment period of at least 4 weeks or at least 8 weeks. In oneembodiment the composition is applied twice a day during a treatmentperiod of at least 4 weeks or 8 weeks.

The step of applying the composition may be accomplished by localizedapplication. In reference to application of the composition, the terms“localized”, “local”, or “locally” mean that the composition isdelivered to the targeted area (such as age spots) while minimizingdelivery to skin surface not requiring treatment. The composition may beapplied and lightly massaged into an area of aging skin. The form of thecomposition or the dermatologically acceptable carrier should beselected to facilitate localized application. While certain embodimentsof the present invention contemplate applying a composition locally toan area, it will be appreciated that compositions of the presentinvention can be applied more generally or broadly to one or more skinsurfaces.

In some embodiments, the composition may be delivered by a variety ofapplicators appropriate for localized and general application. Suchapplicators can include droppers, applicator wands, cotton swabs, or anyother suitable device. Other suitable applicators include SH-0127 penapplicator available from Shya Hsin Plastic Works, Inc., Taiwan andeither the Xpress Tip or liquid filled swab available from SwabPlus,Inc., China. The applicator may be configured to easily apply thecomposition to a sign of aging skin, for example, age spots having anapproximate diameter between about 2 mm and about 10 mm and allowing fora dosed amount of the composition of between about 1 to about 50 μL/cm²or between about 1 to about 5 μL/cm². In another embodiment, thecomposition is applied to the one or more signs of aging (e.g., agespots) and more generally to one or more facial skin surfacescontemporaneously (i.e., over a period of less than 30 minutes or, moretypically, less than 5 minutes).

While some methods described herein contemplate applying thecompositions of the present invention with an applicator, it will beappreciated that applicators are not required and the compositions ofthe present invention can also be applied directly by using one's fingeror in other conventional manners.

In one embodiment, the method comprises the steps of applying a firstcomposition comprising an effective amount of substituted azole to askin surface and of applying a second composition to the skin surface,before or after the first composition. The first and second compositionsmay be any compositions described herein; however, the secondcomposition may optionally comprise an effective amount of thesubstituted azole compound present in the first composition. The secondcomposition may comprise one or more skin tone agents, sunscreenactives, anti-inflammatory agents, or other optional components. Thefirst composition may be generally or locally applied, while the secondcomposition may be generally or locally applied to the skin surfaceincluding the aging skin to which the first composition is applied. Incertain embodiments, the skin surface is facial skin surface whichincludes one or more of the forehead, perioral, chin, periorbital, nose,and cheek skin surfaces. In another embodiment, the first and secondcompositions are applied contemporaneously to at least the cheek,forehead, and chin/perioral skin surfaces. For general application to askin surface and, particularly a facial skin surface, the dosed amountof the first or second composition may be between about 1 to about 50μL/cm² per application (i.e., per single application to the skinsurfaces).

Suitable methods may comprise any one or more of the abovementionedsteps. All of the aforementioned steps are applicable to application,treatment, regulation, and/or improvement of aging skin appearance.

EXAMPLES Example 1 Exemplary Compositions

Table 1 sets forth non-limiting examples of the compositions of thepresent invention. The examples are given solely for the purpose ofillustration and are not to be construed as limitations of the presentinvention, as many variations thereof are possible without departingfrom the spirit and scope of the invention, which would be recognized byone of ordinary skill in the art. In the examples, all concentrationsare listed as weight percent, unless otherwise specified and may excludeminor materials such as diluents, filler, and so forth. The listedformulations, therefore, comprise the listed components and any minormaterials associated with such components. As is apparent to one ofordinary skill in the art, the selection of these minor materials willvary depending on the physical and chemical characteristics of theparticular ingredients selected to make the present invention asdescribed herein.

All examples may be used to improve the appearance of aging skin. Thepresent invention may further relate to a regimen involving thelocalized treatment for one or more signs of aging by a firstcomposition (e.g., Examples A or B) and a more broad or general facialskin treatment by a second composition (e.g., Examples C or D), whichcan be applied before or after the localized treatment to improve aparticular sign of aging skin (e.g., across the entire face).

TABLE 1 Exemplary Compositions Exam- Exam- Exam- Exam- Component/% bywt. ple A ple B ple C ple D 1-phenylimidazole 0.50 1.5 0.00 1.004-phenylimidazole 0.50 0.00 1.50 0.75 N-Acetylglucosamine 0.00 0.00 2.000.00 Hexamidine Diisethionate 0.00 0.00 0.09 0.09 Sepiwhite ™ 0.00 0.000.50 0.50 (Undecylenoyl- phenylalanine, neutralized) (available fromSEPPIC) Sepigel 305 ™ 0.00 0.00 2.00 2.00 (Polyacrylamide + C13-14isoparaffin + laureth-7) (available from SEPPIC) DipotassiumGlycyrrhizate 0.00 0.10 0.10 0.30 Hexamidine Diisethionate 0.00 0.000.09 0.09 Homosalate 0.00 0.00 0.00 9.00 Avobenzone 0.00 0.00 0.00 3.00Octocrylene 0.00 0.00 0.00 2.60 Oxybenzone 0.00 0.00 0.00 1.00Octisalate 0.00 0.00 0.00 4.50 Butylene Glycol 5.50 5.50 5.50 5.50 (CASNo. 107-88-0) Niacinamide 5.00 5.00 5.00 5.00 (CAS No. 98-92-0) Glycerin2.50 2.50 2.50 2.50 (CAS No. 56-81-5) DC 1503 Fluid ™ 2.50 2.50 2.502.50 (available from DowCorning) Lubrajel Oil ™ 1.44 1.44 1.44 1.44(available from Sederma) Phenonip XB ™ 1.25 1.25 1.25 1.25 (availablefrom Clariant) D-panthenol 1.00 1.00 1.00 1.00 (CAS No. 81-13-0)Tospearl 2000 ™ 1.00 1.00 1.00 1.00 (Polymethylsils esquioxane) (CAS No.68554-70-1) (available from GE Silicones/Momentive) DL-Alpha Tocopheryl0.50 0.50 0.50 0.50 Acetate (CAS No. 7695-91-2) Prodew 400 ™ 0.50 0.500.50 0.50 (available from Ajinomoto) Pemulen TR-2 ™ 0.25 0.25 0.25 0.25(Acrylates/C10-30 Alkyl Acrylate Crosspolymer) (available from Noveon)Polysorbate 20 0.25 0.25 0.25 0.25 (CAS No. 9005-64-5) SodiumMetabisulfite 0.25 0.25 0.25 0.25 (CAS No. 7681-57-4) Allantoin 0.200.20 0.20 0.20 (CAS No. 97-59-6) Sodium Hydroxide 0.17 0.17 0.17 0.17(CAS No. 1310-73-2) (50% solution by weight in water) Disodium EDTA 0.100.10 0.10 0.10 (CAS No. 139-33-3) Xanthan Gum (CAS No. 0.05 0.05 0.050.05 11138-66-2) Sodium Hyaluronate 0.01 0.01 0.01 0.01 (CAS No.9067-32-7) Water (CAS No. QS QS QS QS 7732-18-5) TOTAL (% by weight of100.00 100.00 100.00 100.00 total composition)

The compositions of the present invention are generally prepared byconventional methods such as are known in the art of making topicalcompositions. Such methods typically involve mixing of the ingredientsin one or more steps to a relatively uniform state, with or withoutheating, cooling, application of vacuum, and the like. Typically,emulsions are prepared by first mixing the aqueous phase materialsseparately from the fatty phase materials and then combining the twophases as appropriate to yield the desired continuous phase. Thecompositions are preferably prepared such as to optimize stability(e.g., physical stability, chemical stability, photostability) and/ordelivery of the active materials. This optimization may includeappropriate pH (e.g., less than 7), exclusion of materials that cancomplex with the active agent and thus negatively impact stability ordelivery (e.g., exclusion of contaminating iron), use of approaches toprevent complex formation (e.g., appropriate dispersing agents or dualcompartment packaging), use of appropriate photostability approaches(e.g., incorporation of sunscreen/sunblock, use of opaque packaging),etc.

Example 2 In vitro ATRA 4-Hydroxylase Activity Assay to Determine CYPInhibition

All procedures were carried out under minimal light in order to preventdegradation of the retinoid samples.

Microsomal preparation: One lobe of fresh pig liver is obtained (e.g.,at about the time of slaughter from a food-processing company) andimmediately placed in ice cold 15 mM KH2PO4/250 mM sucrose (pH 7.4) andkept on ice during transportation. A 10 g sample of liver is minced andhomogenized in 30 mL of homogenization buffer (15 mM KH2PO4/250 mMsucrose) using a Tekmar homoginizer or equivalent by pulsing 3 timeswith 20 second pulses. This procedure is repeated for a total of 8×10 gsamples of pig liver. The remaining pig liver may be stored at −80° C.The homogenates from the 8 samples are pooled and centrifuged at13,000×g for 20 minutes at 4° C. to remove crude debris. The supernatantis further centrifuged at 100,000×g for 70 minutes at 4° C. Themicrosomal pellets are re-suspended into 50 mL of 150 mM KH2PO4/1 mM DTT(pH 7.4) and 1 mL aliquots are stored at −80° C.

100-150 μg of pig liver microsomal protein in 150 mM KH2PO4 is incubatedat 37° C. in the presence of radiolabeled ATRA and 5 mM NADPH for 90min. The final ATRA concentration is 1 μM, as a combination of[20-Methyl-³H]ATRA and unlabeled ATRA. Initially, radiolabeled ATRA maybe used to assist in validating the method. Once retention times ofretinoid metabolites are identified, unlabeled ATRA is used forscreening. Compounds tested as possible competitive substrates are addedto the assay 10 min prior to the addition of ATRA. Ethanol, containing0.1% butylated hydroxytoluene (BHT) as an antioxidant, is used to stopthe reactions. For recovery of ATRA the pH of reactions are adjusted to3.0 before extraction with 0.1N HCl. Retinoids are extracted from theprotein aqueous phase with 4 mL hexane, 1 ml 100 μg/ml BHT in water (pH3). An additional 4 mL of hexane (pH 3) is used for a second extraction.The organic extractions are pooled, evaporated to dryness using a speedvac, and resuspended in 62.5 μl acetonitrile containing 1 mg/ml BHT.Samples are analyzed by HPLC.HPLC separation of retinoids. A suitableHPLC system (e.g., Waters Corp., Milford Mass.) containing a Vydac 201TP54 column (15 cm×46 mm), multi-wavelength detector (Waters 490) set at350 nm, and a β-RAM detector (IN/US Systems, Tampa, Fla.) is used toseparate retinoids. Mobile phases used for gradient elution of retinoidsare those of Duell et al., J. Clin. Invest. 1992 October; 90(4):1269-1274. Mobile phase A is acetonitrile:0.02 M ammonium acetate:aceticacid (1:1:0.01) and mobile phase B is acetonitrile:0.2M ammoniumacetate:acetic acid (19:1:0.008). At the start of the HPLC run, solventA is run 100% followed by a linear gradient to solvent B at 3 minutes, ashallow gradient to 81% solvent B at 38 minutes, and 100% solvent B at40 minutes. The flow rate is 0.5 mL/min and the total time forseparation is 60 minutes. Effluent from the HPLC column flows directlyinto a flow-through scintillation spectrometer (P-RAM). Because of thesensitivity limitations of the β-RAM spectrometer, it is not used toquantitate peak areas but rather to confirm ATRA and ATRA 4-hydroxylaseactivity. Calculated peaks areas (using Millenium software—Waters Corp.)of ATRA and ATRA metabolites are used to quantify relative activitylevels. Table 2 shows the compounds screened through the in vitro4-hydroxylase assay. Ketoconazole was used as a positive control, whileclimbazole is a known 4-hydroxylase inhibitor marketed as an antifungalactive.

TABLE 2 Screening results from in vitro 4-hydroxylase inhibition assayCompound IC₅₀ (μM) Ketoconazole 8.8 Climbazole 47.5 1-phenylimidazole52.5 4-phenylimidazole 58.8 1-benzylimidazole 77.5 4,5-diphenylimidazole100.0 1-benzyl-2-methylimidazole 307.5 Clotrimazole >5002-phenylimidazole >500

Example 3 In vitro CYP3A4 Inhibition Assay

A commercially available P450-GLO™ Assay kit (Promega Corporation,Madison Wis.) is used to screen various compounds for CYP3A4A inhibitionactivity. CYP3A4A is thought to be one of the primary CYP isoformsresponsible for retinoic acid metabolism in the skin. Three benchmarkagents, liarozole, climbazole, and ketoconazole, were assessed forCYP3A4 inhibition to confirm that the inhibition activity (the IC₅₀ forCYP3A4 inhibition) measured by the assay corresponds to the activityreported by the published literature.

The results set forth in Table 3 show that the substituted azolecompounds having the specific structure set forth herein are CYPinhibitors, and thus function as RAMBAs.

TABLE 3 Screening results from in vitro CYP3A4 Inhibition Assay IC₅₀Structure Compound CAS No. (uM)

Liarizole hydrochloride 145858-50-0 Hit <0.1 uM (0.08-    0.1 uM)

Climbazole  38083-17-9 Hit    0.1 uM

Ketoconozole  65277-42-1 Hit    0.5 uM

Clotrimazole  23593-75-1 Hit    0.3 uM

1-Phenyl- imidazole  7164-98-9 Hit    1 um

4-Phenyl- imidazole   670-95-1 Hit    1.5 uM

Bifonazole  60628-96-8 Hit    0.8 uM

4′-(Imidazol-1 yl) acetophenome  10041-06-2 Hit   0.8 uM

Metyrapone   54-36-4 Hit    3 uM

Piperonyl butoxide   51-03-6 Hit    3 uM

Miconazole  22916-47-8 Hit    5 uM

Miconazole Nitrate  75319-48-1 Hit    5 uM

Fluconazole  86386-73-4 Hit ~10 uM

Piperine   94-62-2 Hit ~10 uM

N-(3- Aminopropyl) imidazole  5036-48-6 no hit >10 uM

Hexamidine diisethionate   659-40-5 no hit >10 uM

3-Benzyladenine 7280-81-1 no hit >10 uM

Histidine   71-00-1 no hit >10 uM

Cimetidine  51481-61-9 Near Hit IC50 >   10 um

Methyl- cholanthrene   56-49-5 Near Hit >10 uM

LY-364947 396129-53-6 no hit >10 uM

Metolachlor  52118-45-2 no hit >10 uM

2-Ethyl-4- methyl- imidazole   931-36-2 no hit >10 uM

6-Chloropurine   87-42-3 no hit >10 uM

L-Glutamine   56-85-9 no hit >10 uM

L-Tryptophan   73-22-3 no hit >10 uM

Benzimidazole   51-17-2 no hit >10 uM

2-Phenylimidazole   670-96-2 no hit >10 uM

2-Phenyl benzimidazole   716-79-0 no hit >10 uM

1-Methylimidazole   616-47-7 no hit >10 uM

Ciprofloxacin HCl  85721-33-1 no hit >10 uM

Erythromycin   114-07-8 no hit >10 uM

1-Vinylimidazole  1072-63-5 no hit >10 uM

2-(2-Chlorophenyl) benzimidazole  3674-96-7 no hit >10 uM

Amitrol   61-82-5 no hit >10 uM

2-Phenyl-5- benzimidazole sulfonic acid  27503-81-7 no hit >10 uM

Diltiazem  42399-41-7 no hit >10 uM

Imidazole 288-32-4 no hit >10 uM

2-Methylimidazole 693-98-1 no hit >10 uM

D-Glutamine  5959-95-5 no hit >10 uM

2-Butyl-4-chloro- 5-(hydroxymethyl) imidazole  79047-41-9 no hit >10 uM

Metazachlor  67129-08-2 no hit >10 uM

L-Arginine   74-79-3 no hit >10 uM

Allopurinol   315-30-0 no hit >10 uM

Glutamylamidoethyl imidazole 169283-81-2 no hit >10 uM

1′-1- Carbonylimidazole   530-62-1 no hit >10 uM

2-Ethylimidazole  1072-62-4 no hit >10 uM

Theophylline   58-55-9 no hit >10 uM

1- Acetylimidazole  2466-76-4 no hit >10 uM

L-Asparigine   70-47-3 no hit >10 uM

2-Butyl-4-chloro- 5-formylimidazole  83857-96-9 no hit >10 uM

β-Ionone   79-77-6 no hit >10 uM

Ectoine  96702-03-3 no hit >10 uM

Clarithromycin  81103-11-9 no hit >10 uM

Nefazodone HCl  83366-9 no hit >10 uM

Carbamazepine   298-46-4 no hit >10 uM

Benomyl  17804-35-2 no hit >10 uM

Immepip dihydrobromide 164391-47-3 no hit >10 uM

Rifampicin  13292-46-1 no hit >10 uM

Cyclosporin A 59865-13-3 no hit >10 uM

Troleandomycin  2751-09-9 no hit >10 uM

Methimazole   60-56-0 no hit >10 uM

Nalidixic acid   389-08-2 no hit >10 uM

Adenine   73-24-5 no hit >10 uM

Fuberidazole  3878-19-1 no hit >10 uM

Kinetin   525-79-1 no hit >10 uM

Example 4 Method of Treatment

A test subject topically applies a composition comprising 0.55%1-phenylimidazole, by weight in a vehicle, to the entire face one to twotimes a day for 8 weeks. After treatment, the subject's facial skinfeels and appears less aged, and the subject notices an improvement inthe appearance of age spots, overall skin tone, and fine lines andwrinkles.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “40 mm” is intended to mean“about 40 mm”.

Every document cited herein, including any cross referenced or relatedpatent or application, is hereby incorporated herein by reference in itsentirety unless expressly excluded or otherwise limited. In particular,U.S. Provisional Application Ser. No. 61/762,546 is incorporated hereinby reference in its entirety. The citation of any document is not anadmission that it is prior art with respect to any invention disclosedor claimed herein or that it alone, or in any combination with any otherreference or references, teaches, suggests or discloses any suchinvention. Further, to the extent that any meaning or definition of aterm in this document conflicts with any meaning or definition of thesame term in a document incorporated by reference, the meaning ordefinition assigned to that term in this document shall govern.

While particular embodiments of the present invention have beenillustrated and described, it would be obvious to those skilled in theart that various other changes and modifications can be made withoutdeparting from the spirit and scope of the invention. It is thereforeintended to cover in the appended claims all such changes andmodifications that are within the scope of this invention.

What is claimed is:
 1. A method of improving the appearance of agingskin comprising: a. identifying a target skin surface in need oftreatment; b. applying to said target skin surface a compositioncomprising: an effective amount of 1-phenylimidazole, 4-phenylimidazoleor a combination thereof; and ii. a dermatologically acceptable carrier;wherein said composition is applied for a period of time sufficient toimprove the appearance of one or more signs of aging.
 2. The method ofclaim 1, wherein said skin surface is a facial skin surface.
 3. Themethod of claim 1, wherein said facial skin surface is a forehead,perioral, chin, periorbital, nose, or cheek skin surface.
 4. The methodof claim 1, wherein said composition additionally comprises a sunscreenactive.
 5. The method of claim 1, wherein said composition additionallycomprises an anti-inflammatory agent.
 6. The method of claim 1, whereinsaid composition further comprises a skin tone agent.
 7. The method ofclaim 6, wherein said skin tone agent is selected from the groupconsisting of vitamin B3 compounds, sugar amines, hexamidine compounds,salicylic acid, 1,3-dihydroxy-4-alkylbenzene, xanthenes, andcombinations thereof.
 8. The method of claim 1, additionally comprisinga step of applying a second composition to the skin surface.
 9. Themethod of claim 1, wherein the second composition comprises a sunscreenactive, an anti-inflammatory agent, a skin tone agent, or a combinationthereof.
 10. The method of claim 9, wherein said skin tone agent isselected from the group consisting of vitamin B3 compounds, sugaramines, hexamidine compounds, salicylic acid,1,3-dihydroxy-4-alkylbenzene, xanthenes, and combinations thereof.